Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (T PMT), an enzyme subject to genetic polymorphism. We investigated the relati onships between the TPMT locus (TPMT activity and genotype) and the pharmac ological response to 6-MP during maintenance therapy of 78 children with ac ute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week ba sis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carry ing a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m(2)/day; P = 0.02) and had on aver age lower leukocyte counts (2834 vs 3398 cells/mm(3); P = 0.003) than patie nts carrying the wild-type TPMT genotype. Higher occurrence of infectious e pisodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patient s. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a hig her percentage of 8 week periods with infectious episodes requiring treatme nt (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or T PMT activity below the group median (P < 0.01). In the last 25 patients enr olled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) c oncentrations were associated with lower leukocyte counts (P = 0.01) but no t with a higher occurrence of infectious episodes. In contrast, higher stea dy-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P < 0.01) and higher occurrence o f infectious episodes (P < 0.001). In conclusion, during maintenance therap y of ALL, children with higher TPMT activity receive a higher 6-MP dosage a nd may have infectious episodes caused by metabolism of 6-MP into methylmer captopurine nucleotides.